Development of pro-angiogenic engineered transcription factors for the treatment of cardiovascular disease.

Gene therapies that use engineered transcription factors to regulate a patient's own endogenous genetic loci offer several advantages over cDNA-based approaches, including the capacity to upregulate all splice variants of a therapeutic gene. Currently, two engineered transcription factors are being developed for use in gene-mediated revascularisation therapies of cardiovascular disease. Both proteins target a powerful, constitutive transcriptional activation module to a defined sequence in the promoter region of vascular endothelial growth factor-A via linkage to an appropriately specific DNA-binding domain, either the basic helix-loop-helix motif of hypoxia-inducible factor-1alpha (HIF-1alpha) or a designed zinc finger protein. Both factors activate the expression of vascular endothelial growth factor-A in cellular studies and induce angiogenesis in animal models of cardiovascular disease. Phase I studies are underway for the HIF-1alpha-based factor and are expected to commence for the zinc finger protein-based factor by the second half of 2004.